Pulsed Release Phenylephrine Dosage Forms

ABSTRACT

A multi-particle dosage form that can deliver phenylephrine in controlled pulsed doses. The dosage form can contain an immediate release form that can contain phenylephrine or a salt thereof and a plurality of delayed release particles with a coating that can contain phenylephrine or salt thereof and a pH sensitive coating.

FIELD OF THE INVENTION

The present invention is generally related to a dosage form consistingof immediate and delayed release phenylephrine portions and moreparticularly, where the delayed release of phenylephrine is pulsatile.

BACKGROUND OF THE INVENTION

Decongestants are commonly used to relieve nasal congestion and acommonly used decongestant is phenylephrine. Phenylephrine is widelyavailable to consumers as an over-the-counter (OTC) drug.

One problem for immediate release dosage forms containing phenylephrineis that in order for it to be most effective, it must be takenfrequently. The current U.S. Monograph for an oral dosage formcomprising phenylephrine hydrochloride is ten milligrams every fourhours. Consumers find it inconvenient to dose every four hours andfrequently miss doses, especially mid-day doses, which can result inpoor symptomatic relief.

Furthermore, the short time period between doses makes it difficult tocombine phenylephrine with other drug actives, in particular activesthat are commonly used in multi-symptom relief cold/flu products, whichhave longer dosing intervals. Therefore, consumers have to take multipledosage forms and dose several times a day at various intervals toexperience the optimal relief of their cold/flu symptoms.

One of the reasons for frequent dosing is because phenylephrine issubject to high first pass metabolism and a short half-life. Upon oraladministration, phenylephrine is rapidly metabolized and is subsequentlyconjugated into sulfate and glucuronide forms. However, the therapeuticdecongestant activity is attributed to the portion of the phenylephrinethat is not metabolized and stays as the unconjugated parent active.Accordingly, it is of benefit to maximize the duration of time of theunconjugated active form present in bloodstream after oraladministration.

There have been several attempts to modify the release of phenylephrinein order to prolong the dosing interval. Many approaches related to themodified release of phenylephrine focus on dual release mechanismscomprising an immediate release form coupled with an extendedfirst-order or zero-order extended phase of release. A problem withthese bi-modal approaches is that during the extended release phase, lowlevels of unconjugated phenylephrine active are likely to be present inthe bloodstream due to rapid first pass metabolism. An alternateapproach would be a pulsatile dose form that releases active atdifferent regions in the intestine and can mimic immediate releasedosage forms administered every 4 hours. Such a dosage form would bebeneficial to the consumer and allow for more effective and convenientdosing.

As such, there remains a need in the area of consumer selected OTCtherapies for improved options for the treatment of symptoms associatedwith the common cold (rhinovirus), influenza, or environmentalallergies. In particular, there exists a need for a convenient longeracting phenylephrine dosage form that can provide relief over anextended period of time relative to current therapies.

SUMMARY OF THE INVENTION

A dose of a multi-particle oral dosage form for the delivery ofphenylephrine in controlled pulsed doses comprising: (a) an immediaterelease form comprising phenylephrine or a salt thereof; and (b) aplurality of delayed release particles comprising a coating comprisingphenylephrine or salt thereof and a pH sensitive coating comprising apolymer; wherein the AUC meets or exceeds the AUC for two 10 mgimmediate release phenylephrine doses taken four hours apart.

A multi-particle oral dosage form for the delivery of phenylephrine incontrolled pulsed doses comprising: (a) an immediate release formcomprising phenylephrine or a salt thereof; and (b) a plurality ofdelayed release particles comprising a coating containing phenylephrineor salt thereof and a pH sensitive coating comprising a polymer; whereina lag time as determined by the Krebs Buffer Method is from about 1 hourto about 4 hours.

BRIEF DESCRIPTION OF THE DRAWINGS

While the specification concludes with claims particularly pointing outand distinctly claiming the subject matter of the present invention, itis believed that the invention can be more readily understood from thefollowing description taken in connection with the accompanyingdrawings, in which:

FIG. 1 is a schematic of an immediate release particle;

FIG. 2 is a schematic of a delayed release particle;

FIG. 3 shows the mean concentration of unconjugated phenylephrine, invivo over time for different formulation prototypes;

FIG. 4 shows the mean concentration of total phenylephrine, in vivo overtime for different formulation prototypes;

FIG. 5 shows the mean percent dissolved phenylephrine, in vitro usingthe Krebs Buffer Dissolution Method, over time for different formulationprototypes;

FIG. 6 shows a computer model of a marketed phenylephrine product takenevery four hours and an eight hour delayed release prototype;

FIG. 7 shows a computer model of a marketed phenylephrine product takenevery four hours and an optimal eight hour delayed release prototypethat is substantially bioequivalent;

FIG. 8 shows a computer model of a marketed phenylephrine product takenevery four hours and exceeds bioequivalence;

FIGS. 9A, 9B, 9C, and 9D show digital photographs of delayed releaseparticles under a total magnification of 40×;

FIGS. 10A, 10B, 10C, and 10D show digital photographs of delayed releaseparticles under a total magnification of 40×; and

FIGS. 11A and 11B show exemplary images of the field of view used in theSmoothness Test Method.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a multi-particle, oral dose formdesigned for an immediate release of phenylephrine hydrochloride (PE)followed by one or more delayed pulses. In one example, one or moredelayed pulses are formulated so the phenylephrine is released in adifferent region of the gastrointestinal tract in order to provide anextended period of congestion relief. In one example, the delayeddelivery doses are enteric coated and designed to release thephenylephrine in the distal small intestine. While not wishing to bebound by theory, it is believed that delivery to the distal smallintestine is effective because the effects of the operative metabolicenzymes are reduced, ultimately resulting in an optimal amount ofunconjugated phenylephrine in the blood and longer duration of dosing.In this way, therapeutic levels of phenylephrine can be delivered at theappropriate dose, intestinal region, and time interval to provideeffective relief over an extended period of time.

The multi-particle, solid oral dose form can be a tablet, a sachet, or acapsule, containing phenylephrine which can be administered every 6, 8,or 12 hours to provide extended congestion relief to a patient. In oneexample, the dose form can meet or exceed the bioavailability and/orbioequivalence as compared to two or three immediate release doses ofphenylephrine taken at four hour time intervals.

As used herein, “AUC” refers to the area under the concentration-timecurve from time of dosing up to a time point, calculated by the lineartrapezoidal rule. AUC is a parameter that shows the cumulative plasmaconcentration of a drug over time, and is an indicator of the totalamount and availability of a drug. “AUC(0-t)” is defined as AUC for anyvalue of time up to t hours. In a one example, t is 12 hours (referredto herein as AUC(0-12)), other examples can include AUC(0-6) andAUC(0-8). “AUC(0-infin)” is defined as calculated AUC extrapolated toinfinity. AUC(0-infin), is calculated as equal to AUC_(last)+Ct/lambdaz, wherein AUC_(last) is the AUC until the time point of last measurableconcentration, Ct is the last measurable plasma concentration, andlambda z is the terminal phase rate constant. Terminal phase rateconstant lambda z is derived from the slope of the drugconcentration-time curve using linear regression on terminal data pointsof the curve.

As used herein, “bioavailability” refers to a rate and extent to whichthe active drug ingredient or therapeutic moiety is absorbed from a drugproduct and becomes available for therapeutic action. In one example thedrug ingredient can be phenylephrine and it can reach the systemiccirculation and can be available at its site of action.

As used herein, “bioequivalent” and “bioequivalency” refers to a dosageform whose rate and extent of absorption do not show a significantdifference when administered under similar experimental conditions, to asingle dose or multiple doses of a currently available product. Somedosage forms may be equivalent in the extent of their absorption but notin their rate of absorption and yet may be considered bioequivalentbecause such differences in the rate of absorption are intentional andare reflected in the labeling, are not essential to the attainment ofeffective body drug concentrations on chronic use, or are consideredmedically insignificant for the particular drug product studied.

In one example, a pulsatile PE dose form that at minimum exposure, canmeet or exceed the bioequivalency (80-125% AUC) of a commerciallyavailable, immediate release PE dose taken at 4 hour intervals.

As used herein, “conjugated phenylephrine” refers to phenylephrine thatis metabolized. This means that the phenylephrine has been conjugated(i.e. chemically altered) by an enzyme. The enzymes which conjugatephenylephrine can include sulfotransferase orUDP-glucuronosyltransferase.

As used herein “delayed release” refers to a particle, a plurality ofparticles, or a dosage form where the drug active (or actives) arereleased at a time other than immediately following oral administration.In one example, a delayed release particle, plurality of particles, ordosage form has been deliberately modified such that the majority of thedrug active that is contained in or on the particle, plurality ofparticles, or dosage form is released or absorbed into the blood plasmasome period of time after administration. One advantage of a delayedrelease dosage form is that it can be formulated to release an activeafter a specified time period or upon encountering the properenvironment (for example, release based on pH, enzymatic activity, orsolubility). In one example, the delayed release particles have anenteric coating, which means that the particle coatings are pH sensitiveand the benefit is not experienced by the user until the particle(s) ordosage form reaches certain regions of the intestine. In one example, adelayed release particle, plurality of particles, or a dosage form canbe taken in combination with an immediate release for, which can includean immediate release particle, plurality of particles or other dosageform. In one example, the dosage form or particle(s) do not deliver anactive slowly over an extended duration of time, instead the particlescan be designed to rapidly or immediately deliver an active after adelay period.

As used herein, “dissolve” refers to disintegrating, dispersing and/orpassing into solution.

As used herein, “dose” or “dosage unit” refers to a dosage formcontaining an amount of a drug active suitable for administration on asingle occasion, according to sound medical practice. The dosage formmay include a variety of orally administered dosage forms. Non-limitingexamples of dosage forms can include particles suspended in a liquidformulation, a solid in a gelatin or foam, or a solid dose in the formof a tablet, powder, granules, pellets, microspheres, nanospheres,beads, or nonpareils, and combinations thereof. In one example, thedosage form is a tablet or a capsule. In another example, the dosageform is a capsule containing delayed release particles and optionally animmediate release form and excipients. Dosage forms can be orallyadministered and are typically swallowed immediately, slowly dissolvedin the mouth, or chewed.

As used herein, “extended release” refers to a particle, a plurality ofparticles, or a dosage unit that allows a reduction in dosing frequencyas compared to that presented by a conventional dosage form, e.g., asolution or an immediate release dosage form. In one example, anextended release dosage form can be deliberately modified wherein theparticle, plurality of particles, or dosage form is formulated in such amanner as to make the drug active available over an extended period oftime following administration. One example of an extended releaseparticle, plurality of particles or dosage form is a delayed releasedosage form. Another example of an extended release particle, pluralityof particles or dosage form can be pulsatile release dosage forms orparticle(s).

As used herein, “immediate release” refers to a particle, a plurality ofparticles, or a dosage form wherein no deliberate effort has been madeto modify the release rate and in the case of capsules, tablets, andparticles the inclusion of a disintegrating agent is not interpreted asa modification.

As used herein, “PK profile” refers to a pharmacokinetic profile whichis the concentration of a drug, such as unconjugated phenylephrine, inplasma over time.

As used herein, “pulsatile release” refers to the phenylephrine beingreleased at two or more distinct time periods following ingestion. Inone example, the dosage form can have an immediate release form, whichcan be a plurality of immediate release particles, and a plurality ofdelayed release particles which results in an immediate release of thefirst pulse of phenylephrine after administration of the dosage form tothe user and a second pulse when the delayed release particles enter thehigher pH environment of the small intestine.

As used herein, the term “substantially equivalent” refers to withinabout 60%, in another example within about 70%, in another examplewithin about 75%, in another example within about 80%, in anotherexample within about 85%, in another within about 90%, in anotherexample within about 93%, in another example within about 95%, inanother example within about 98%, in another example within about 102%,in another example within about 105%, in another example within about107%, in another example within about 110%, in another example withinabout 115%, in another example within about 120%, in another examplewithin about 125%, in another example within about 130%, and in anotherexample within about 140%. Substantially equivalent can refer to, but isnot limited to, the PK profile, the C_(max), and AUC. As used herein,the term “total phenylephrine” refers to the amount of conjugatedphenylephrine and unconjugated phenylephrine.

As used herein, the term “treat” or “treating” includes preventing,alleviating, ameliorating, inhibiting, or mitigating one or more healthconditions in a mammal. Non-limiting examples of health conditions caninclude respiratory conditions.

As used herein, “unconjugated phenylephrine” refers to phenylephrinethat is unmetabolized and is the therapeutically active form ofphenylephrine. Unmetabolized phenylephrine is phenylephrine that hasentered the body of the user and is not chemically altered at the timeof absorption into the blood plasma or later.

As used herein, the articles “a” and “an” are understood to mean one ormore of the material that is claimed or described, for example, “anacrylic acid ester co-polymer” or “a multi-particle dosage form”.

All percentages, parts and ratios as used herein are by weight of thedosage form, unless otherwise specified. All such weights as theypertain to listed ingredients are based on the active level and,therefore do not include solvents or by-products that may be included incommercially available materials, unless otherwise specified.

The dosage form, process and methods of the present invention cancontain, consist of, or consist essentially of, the essential elementsand limitations of the invention described herein, as well as anyadditional or optional ingredients, components, or limitations describedherein or otherwise useful in dosage forms intended for use orconsumption by humans.

FIG. 1 shows a schematic of an immediate release particle 1. Immediaterelease particle 1 can comprise a core 2, a phenylephrine coating 3, andoptionally a separation coating 4. In one example, the phenylephrinecoating 3 can dissolve or start to dissolve after it reaches thestomach.

FIG. 2 shows a schematic of a delayed release particle 10. Delayedrelease particle 10 comprises a core 12, phenylephrine coating 13,optionally separation coating 14, pH sensitive coating 15, andoptionally anti-caking coating 16.

In one example, the immediate release particles and/or the delayedrelease particles can have a separation coating. For immediate releaseparticles the separation coating can help limit friability in handlingthe particles. Additionally, for delayed release particles theseparation coating can separate the highly soluble phenylephrine layerfrom the pH sensitive coating. If phenylephrine leaches or migrates intothe pH sensitive coating then this may result in premature drugdissolution. Non-limiting examples of separation coatings can includetalc, polyvinyl alcohol-polyethylene glycol graft co-polymer(commercially available as Kollicoat® IR, from BASF, Tarrytown, N.J.),hydroxypropyly methylcellulose, hydroxypropyl cellulsoe,polyvinylpyrrolidine, and combinations thereof. In another example, theseparation coating can be a pH independent polymer. In another example,the separation coating can be a pH independent polymer. In one example,the separation coating can contain polyvinyl alcohol.

In one example, the anti-caking coating can be sprayed onto the delayedrelease particles to prevent the particles from sticking together duringstorage. In another example, the immediate release particles can have ananti-caking coating. If the particles stick together, this can causeuneven dissolution, which alters the carefully timed release of thephenylephrine. The anti-caking coating can be any material that preventsthe particles from sticking together. In one example, the anti-cakingcoating can be clear and in another example the anti-caking coating canbe translucent. In another example, the anti-caking coating can beopaque. In another example, the anti-caking coating can be a whitepowder. In another example, the anti-caking coating can contain a color.In one example, the anti-caking coating can contain a fine particulatethat has a high relatively high surface area and is insoluble in water.In one example the surfaces area is greater than about 100 m²/g, inanother example greater than about 150 m²/g, in another example greaterthan about 175 m²/g, and in another example greater than about 200 m²/g.In one example, the weight percent (wt. %) increase of the particleafter the anti-caking coating is added can be from about 0.1% to about5%, in another example from about 0.15% to about 3%, and in anotherexample from about 0.2% to about 2%.

Non-limiting examples of anti-caking coatings can include talc, sodiumferrocyanide, potassium ferrocyanide, calcium carbonate, magnesiumcarbonate, silicon dioxide, hydrophilic fumed silica (commerciallyavailable as Aerosil® 200, Evonik Industries, Parsippany, N.J.,precipitated silica, sodium aluminosilicate, and combinations thereof.In one example, the anti-caking coating contains hydrophilic fumedsilica. In another example, the anti-caking coating can contain a thinaqueous coating based on glycerol monostearate and/or hydroxypropylmethylcellulose. In another example, the anti-caking coating can containpolyvinyl alcohol, and/or polyvinyl alcohol-polyethylene glycol graftcopolymer (commercially available as Kollicoat® IR, BASF, Tarrytown,N.J.).

Owing to the different pH environments and variability within the GItract, it can be difficult to predict the level and type of polymerrequired to affect the desired pulsed release characteristics. In oneexample, of a pulsed release phenylephrine dosage form, the polymertype, coating level, particle population ratios, and individual doselevels are carefully selected and tailored based on dissolution andpharmacokinetic parameters to achieve a dosage form with a PK profilethat meets or exceeds bioequivalency and/or bioavailability relative tosequentially dosed immediate release forms of phenylephrine taken atregular, usually four hour, intervals.

An example, may include a mixture of immediate release forms and delayedrelease particles at dosages that are not bioequivalent to sequentiallydosed immediate release forms but can nevertheless be registered in theUS and other geographies through appropriately designed clinicalpharmacokinetic, safety and/or efficacy trials or additional supportingdata. Another example can include a mixture of immediate release anddelayed release particles at dosages that are substantiallybioequivalent to two or three sequentially dosed immediate releaseddosage forms.

The PK profile examines the time course in vivo after phenylephrine hasbeen administered and includes the C_(max), AUC, T_(lag), and T_(max).C_(max) is the maximal plasma concentration observed. T_(max) is thetime to reach C_(max). T_(lag) is the lag time prior to the firstquantifiable plasma concentration level.

PK parameters for unconjugated and total PE from an in vivo study thatevaluated four delayed release treatments to a commercially availablephenylephrine product are shown in Tables 1 and 2 and FIGS. 3 and 4. InTables 1 and 2 and FIGS. 3 and 4, Treatment 1 corresponds to Example 2,Treatment 2 corresponds to Example 4, Treatment 3 corresponds to Example3, and Treatment 4 corresponds to Example 1. All Examples are describedhereafter. Treatments 5 and 6 used a commercially availablephenylephrine product, Equate® Non-Drowsy Suphedrine PE (Batch No.1DE1383). Treatment 5 was administered once at t=0 hours. Treatment 6was administered three times, once at t=0, once at t=4, and then againat t=8.

Table 1, which is detailed below, shows a summary of the key PKparameters in vivo, C_(max), AUC_(last), t_(lag), and t_(max), forunconjugated PE.

TABLE 1 Treatment C_(max) (pg/mL) AUC_(last) (pg · hr/mL) t_(lag) (h)t_(max) (h) 1 1294 (75.4) 1481 (83.4) 1 (0.5, 2.5) 3 (2, 4) 2 1728(95.4) 1872 (57.8) 2.5 (1, 3.5) 3.5 (1.5, 8) 3 1978 (77.9) 2325 (60.8)2.5 (0.3, 4.5) 3.5 (2.5, 5.5) 4 1444 (64.5) 1824 (41.5) 2 (1, 3) 3.25(2.5, 4) 5  689 (54.4)  632 (21.0) 0 (0, 0) 0.5 (0.25, 0.53) 6  798(33.4) 2210 (20.9) 0 (0, 0) 0.5 (0.25, 1)* Mean (CV %) for C_(max), AUCand Median (range) for t_(lag) and t_(max) *For Treatment 6, t_(max)values displayed are corrected for dosing time

Table 2, which is detailed below, shows a summary of the key PKparameters in vivo, C_(max), AUC_(last), t_(lag), and t_(max), for totalPE.

TABLE 2 Ratio of AUC_(last) of unconjugated to AUC_(last) totalTreatment C_(max) (ng/mL) AUC_(last) (ng · hr/mL) phenylephrine t_(lag)(h) t_(max) (h) 1 139 (29.6) 479 (22.1)  0.003 (103.9) 0.5 (0.25, 0.5) 3(2, 5) 2  63 (50.0) 269 (38.3) 0.008 (72.6) 2 (1, 3) 4 (2, 8) 3  73(41.1) 303 (26.1) 0.008 (73.0) 0.5 (0.25, 0.5) 4 (3, 6.5) 4  75 (54.4)323 (33.5) 0.006 (52.4) 0.358 (0.25, 0.5) 4 (2.5, 5.5) 5 163 (20.7) 570(15.6) 0.001 (30.4) 0 (0, 0) 1 (0.5, 2.0) 6 206 (17.2) 1795 (22.7) 0.001 (22.2) 0 (0, 0) 1.5 (1, 2.5) Mean (CV %) for C_(max), AUC, andratio and Median (range) for t_(lag) and t_(max) *For Treatment 6,t_(max) values displayed are corrected for dosing time.

FIG. 3 shows the mean concentration of unconjugated phenylephrine overtime for different treatments. One example of a desired treatment can beone where the second pulse has a substantially equivalent C_(max),AUC_(last), t_(lag), and t_(max) to Treatment 6.

FIG. 4 shows the mean concentration of total phenylephrine over time fordifferent treatments. One example of a desired treatment can be onewhere the second pulse has a substantially equivalent C_(max),AUC_(last), t_(lag), and t_(max) to Treatment 6.

FIG. 8 shows a computer model of a marketed phenylephrine product takenevery four hours and exceeds bioequivalence. Although this exampleexceeds bioequivalence, it can still be deemed to be safe and effective.

The treatments demonstrate that the ratio of AUC_(last) unconjugated toAUC_(last) of total phenylephrine is higher for the treatments with a pHsensitive coating than Treatments 5 and 6 which do not have a pHsensitive coating. In one example, the ratio for the treatments with apH sensitive coating is from twofold to tenfold greater than the ratioof a treatment without a pH sensitive coating, in another examplefourfold to eightfold greater, and in another example fivefold tosevenfold greater. In one example, the ratio for the treatment with a pHsensitive coating is six fold greater than the ratio of a treatmentwithout a pH sensitive coating.

The mean concentration of phenylephrine of Treatment 4 is the closest toTreatment 6 as compared to Treatments 1, 2, and 3. Thus, Treatment 4 wasused as a starting point to develop additional prototypes. However, thephenylephrine was released prematurely from Treatment 4 and is thus notideal. Thus, new prototypes were designed with thicker pH sensitivecoatings, to further delay the lag time. It was estimated that it wouldbe most desirable to further delay the lag time by an additional 90-120minutes. In one example, a lower dose of phenylephrine was used toadjust the C_(max) and AUC values to match IR 10 mg doses. Otherexamples could include 10 mg or higher doses of PE for the second pulse,to achieve higher systemic exposures relative to the IR treatment.

FIG. 5 shows the amount of phenylephrine released, in vitro using theKrebs Buffer Dissolution Method, as described below, over time withdifferent formulation prototypes. While not wishing to be bound bytheory, it is believed that the Krebs buffer, which containsbicarbonate, is a better approximation for the conditions in thedigestive tract than other dissolution methods, which use phosphatebuffers, and can lead to better approximations for delayed releaseparticles. The prototypes shown in FIG. 5 correspond to Examples 6-11,herein.

The amount of phenylephrine released was calculated using an HPLC Assay,as described below, and can be seen in FIG. 5. When the amount ofphenylephrine released is greater than the acid limit, which is about10%, this is the lag time.

In one example, the lag time as determined by following the Krebs BufferMethod is from about 0.5 hours to about 6 hours, in another example fromabout 1 hour to about 4 hours, in another example from about 1.25 hoursto about 3 hours, and in another example from about 1.5 hours to about2.5 hours.

TABLE 3 Amount % wt gain of pH Prototype lag time Delayed releasephenylephrine sensitive in Krebs Buffer particles (mg) coating (hours)Ex. 5 3 50 2 Ex. 6 5 40 1.5 Ex. 7 5 50 2 Ex. 9 5 60 2.4 Ex. 10 7 40 1.5Ex. 11 7 50 2

The PK profile for a 10 milligram (mg) immediate-release dose ofphenylephrine hydrochloride and 10 mg of phenylephrine hydrochloridedosed every four hours was determined in a clinical study and used inthe computer modeling of desired PK profiles. In one example, the PKprofile was determined by using computer modeling to compare the AUC ofa delayed release dosage form to the PK profile of two or threeimmediate release phenylephrine dosage forms that was dosed every fourhours. In another example, the t_(lag) can be adjusted to adjust thedosing frequency as well as the desired level of phenylephrine.

FIG. 6 is a computer model that shows a marketed phenylephrine producttaken every four hours and an eight hour delayed release prototype wherethe t_(max) values for the second peak do not coincide with the secondpeak of the immediate release prototype. In FIG. 6, in the first pulse,the C_(max) for both the prototype and the marketed product are thesame. However, the second pulse for the prototype is too early whichcauses the concentration of unconjugated phenylephrine in the plasma tobe higher than that of the immediate release treatment.

FIG. 7 is a computer model that shows a marketed phenylephrine producttaken every four hours and a desirable eight hour delayed releaseprototype. In FIG. 7, the first pulse for both the prototype and themarketed product are the same and the C_(max) of the second pulse forboth the prototype and the marketed product are substantiallyequivalent. Therefore, in FIG. 7, the PK profile for the prototype issubstantially equivalent to the PK profile for the marketed product.

In one example, the dosage form can be administered every six hours, inanother example every seven hours, in another example every eight hours,in another example every nine hours, in another example every ten hours,and in another example every twelve hours.

In one example, the AUC for a dosage form that can be administered everyeight hours can meet or exceed the AUC for two 10 mg immediate releasedoses administered every four hours. In another example, the AUC for adosage form that can be administered every twelve hours can meet orexceed the AUC for three 10 mg immediate release doses administeredevery four hours. In such a dosage form, C_(max) for the novel form canmeet or exceed the immediate release form dosed every 4 hours for atotal of two or three doses.

In another example, the AUC for a dosage form that can be administeredevery eight hours can be substantially equivalent or greater than theAUC for two 10 mg immediate release doses administered every four hours.In another example, the AUC for a dosage form that can be administeredevery twelve hours can be substantially equivalent or greater than theAUC for three 10 mg immediate release doses administered every fourhours. In such a dosage form, C_(max) for the novel form can also besubstantially equivalent or greater than the immediate release formdosed every 4 hours for a total of two or three doses.

In another example, the dosage form can have a higher AUC and/or C_(max)for the immediate release particles and the delayed release particles ascompared to the AUC and/or C_(max) for 10 mg immediate release dosesadministered every four hours.

In order to provide delayed release phenylephrine dosage forms, thedosage form can be properly formulated.

The dosage form can contain a plurality of particles. The term particleis not meant to be limiting and can include microcrystals,micro-particles, beads, microbeads, powders, granules, pellets,micropellets, nonpareil seeds, and microcapsules. In one example theparticle is from about 200 μm to about 1500 μm in its longest dimension,in another example about 300 μm to about 1000 μm, in another exampleabout 400 μm to about 800 μm, and in another example about 500 μm toabout 725 μm. In another example, the particles are spherical orsubstantially spherical.

In another example, the delayed release particles can be substantiallysmooth. If the delayed release particles are not smooth, for instance ifthey are spiked or have a rough surface appearance, the dissolution canbe altered. If the particles are spiked or have a rough surface, therelease of phenylephrine can be early as the phenylephrine can leak outof the portions of the particles that have the thinnest coating level.In one example, the particles are substantially smooth, as visuallyperceived under a microscope with a total magnification of 40×. As usedherein, “visually perceived under a microscope” means that a humanviewer can visually discern that the particle is smooth and the surfacehas an appearance that is substantially similar to a particle without apH sensitive coating under a properly focused microscope with a totalmagnification of 40×. FIGS. 9 A, B, C and D show digital photographs ofparticles that are not substantially smooth as can be visually perceivedunder a microscope with a total magnification of 40×. FIGS. 10 A, B, C,and D show digital photographs of particles that are substantiallysmooth as can be visually perceived under a microscope with a totalmagnification of 40×. The substantially smooth particles can beout-of-round and still smooth.

In another example, smoothness can be determined by the Smoothness TestMethod, as described hereafter. In one example, the particles can have amean circularity from about 0.70 to about 1, in another example fromabout 0.75 to about 1, in another example from about 0.8 to about 1, inanother example from about 0.85 to about 1, in another example fromabout 0.90 to about 1, and in another example from about 0.95 toabout 1. In another example particles can have a mean circularity fromabout 0.72 to about 0.95, to about 0.78 to about 0.93, and from about0.82 to about 0.89.

In one example, the dosage form can deliver a therapeutic blood plasmaconcentration of unconjugated phenylephrine for at least 6 hours, inanother example for at least 8 hours, in another example for at least 10hours, and in another example for at least 12 hours.

The core of the particles in the present dose form can contain anypharmaceutically suitable material. Non-limiting examples of corematerials can consist of microcrystalline cellulose, sugars, starches,polymers, and combinations thereof. In one example, the core can bemicrocrystalline cellulose spheres marketed under the tradename“Cellets®” available from Glatt® Air Techniques Inc., Ramsey, N.J. Inone example, the microcrystalline cellulose spheres can have a diameterof about 500 μm to about 710 μm and a bulk density of about 0.7 g/cc toabout 0.9 g/cc.

The delayed release particles can contain a pH sensitive coating whichmeans that the coating dissolves when it is immersed in a particular pH,which can be basic or acidic. In one example the pH sensitive coating isan enteric coating. It can be important for the coating to be theappropriate thickness or appropriate weight percentage. If the coatingis too thin or the weight percentage is too low, then the phenylephrinecan be released too early relative and the lag time can be shorter thanrequired. One problem with releasing the phenylephrine too early is thatthe doses can be too close together and the user may not have asustained level of unconjugated phenylephrine for the intended duration.One example of phenylephrine being released too early can be seen inFIG. 6.

If the coating is too thick or if the weight percentage is too high,then the phenylephrine can be released suboptimally with respect toachieving the intended 6-12 hour duration of dosing. If thephenylephrine is released too distally in the small intestine then theremay not be enough time for the phenylephrine to enter the blood streambefore entering the colon. While not wishing to be bound by theory, thecolon may not have enough liquid to allow the dissolution ofphenylephrine and a reduced surface area to allow for systemicabsorption. Therefore it can be advantageous for significant dissolutionof the dose form and active to occur prior to migration into the colon.

The weight percent (wt. %) increase of the particle after the pHsensitive coating is added can be from about 15 wt. % to about a 65 wt.% increase, in another example from about a 25 wt. % to about a 55 wt.%, and in another example from about a 35 wt. % to about a 45 wt. %.

In another example, the wt. % increase after the pH sensitive coating isadded can be from about 25 wt. % to about a 75 wt. % increase, inanother example from about a 35 wt. % to about a 45 wt. %, and inanother example from about a 45 wt. % to about a 55 wt. %.

In another example, the wt. % increase after the pH sensitive coating isadded can be from about 40 wt. % to about a 80 wt. % increase, inanother example from about a 50 wt. % to about a 75 wt. %, and inanother example from about a 55 wt. % to about a 65 wt. %.

In another example, the wt. % increase after the pH sensitive coating isadded is from 20 wt. % to about 60 wt. %, in another example from about30 wt. % to about 55 wt. %, in another example from about 40 wt. % toabout 30 wt. %, in another example from about 42 wt. % to about 48 wt.%, in another example from about 44 wt. % to about 46 wt. %, and inanother example about 45 wt. %. the wt. % increase after the pHsensitive coating is added is from about 10 wt. % to about 50 wt. %, inanother example from about 20 wt. % to about 45 wt. %, in anotherexample from about 30 wt. % to about 40 wt. %, in another example fromabout 32 wt. % to about 38 wt. %, in another example from about 34 wt. %to about 36 wt. %, and in another example about 35 wt. %. In anotherexample, the wt. % increase after the pH sensitive coating is added isfrom about 30 wt. % to about 50 wt. % and in another example from about35 wt. % to about 45 wt. %.

In another example, the delayed release particles can optionallycomprise from about a 5 wt. % to about a 55 wt. % pH sensitive coating,by weight of the particle, in another example from about a 10 wt. % toabout a 45 wt. %, and in another example from about a 15 wt. % to abouta 35 wt. %.

The pH sensitive coating can be an enteric coating. In one example, thepH sensitive coating can be degradable in the small intestine at a pH ofat least 5.5 and in another example the pH coating can be degradablewhen the pH is at least 7.0. In any event, in one example, the pHsensitive coating can avoid degradation premature phenylephrinedissolution in the low pH in the stomach.

-   -   The pH sensitive coating can contain one or more polymers alone        or in combination with water soluble or insoluble polymers. The        pH sensitive coating can contain any chemically stable,        biocompatible polymer. In one example, the pH sensitive coating        has a molecular weight of from 100,000 g/mol to 600,000 g/mol,        in another example 150,000 g/mol to 500,000 g/mol, in another        example 200,000 g/mol to 400,000 g/mol, in another example        225,000 g/mol to 350,000 g/mol, and in another example 250,000        g/mol to 300,000 g/mol.

Non-limiting examples of polymers can include cellulose esters andderivatives, acrylate copolymers, hypromellose acetate succinate,polyvinyl acetates and derivatives (commercially available asKollicoat®, from BASF, Tarrytown, N.J.), shellac, and combinationsthereof.

Non-limiting examples of cellulose esters and derivatives can includecellulose acetate phthalate, hydroxypropyl methylcellulose phthalate(HPMCP), hydroxypropyl methylcellulose acetate succinate, celluloseacetate tetrahydrophthalate, cellulose acetate hexahydrophthalate,hydroxypropyl cellulose acetate succinate, and combinations thereof.

Non-limiting examples of acrylate copolymers can includemethyl-methacrylate esters copolymerized with methacrylic acid, acrylicacid and esters copolymerized with methacrylic acid and esters,ammonio-containing acrylate copolymers, and combinations thereof.

In one example, the polymer can be an anionic copolymer based on methylacrylate, methyl methacrylate, and methacrylic acid. In one example, thecoating can contain Poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 polymer marketed under thetradename “Eudragit® FS30D”, available from Evonik Industries,Darmstadt, Germany. In another example, the coating can further comprisePoly(methacrylic acid-co-ethyl acrylate) 1:1 polymer, marketed under thetradename “Eudragit® L30D”, commercially available from Evonik,Darmstadt, Germany.

In one example, the pH sensitive coating can contain both Eudragit®FS30D and Eudragit® L30D. In one example, the pH sensitive coating cancontain from 50% to 95% FS30D, by weight of the total Eudragit®, inanother example 60% to 90%, and in another example 70% to 85%. In oneexample, the pH sensitive coating can contain 85% FS30D and 15% L30D byweight of the Eudragit®, in another example the pH sensitive coating cancontain 90% FS30D and 10% L30D.

In one example, the pH sensitive coating can contain more than onepolymer that can be mixed at any ratio to control where thephenylephrine is released.

In one example, the immediate release particles can have a polymercoating, which is not an enteric coating and can dissolve upon hittingthe stomach.

In another example, the % of phenylephrine in the dosage form and/or theimmediate release dosage forms and/or the delayed release particles cancontain from about 2% to about 20%, in another example from about 5% toabout 15%, in another example from about 7% to about 12%, in anotherexample from about 8% to about 10%, and in another example from about 7%to about 9%. In another example, the % of phenylephrine in the dosageform and/or the immediate release dosage forms and/or the delayedrelease particles can be greater than about 5%, in another examplegreater than about 6%, in another example greater than about 7%, inanother example greater than about 8%, in another example greater thanabout 9%, in another example greater than about 10%, in another examplegreater than about 11%, and in another example greater than about 12%.In another example, the % of phenylephrine in the dosage form and/or theimmediate release dosage forms and/or the delayed release particles canbe less than about 25%, in another example less than about 20%, inanother example less than about 15%, in another example less than about12%, and in another example less than about 10%. In another example, the% of phenylephrine in the dosage form and/or the immediate releasedosage forms and/or the delayed release particles can be from about 8%to about 30%, in another example from about 10% to about 25%, in anotherexample from about 12% to about 20%, and in another example from about13% to about 18%.

The ratio of immediate release particles or other immediate releaseforms to delayed release particles can vary. In one example, eachimmediate release form can contain the same amount of phenylephrine aseach delayed release particle and the ratio of immediate release form todelayed release particle can be adjusted to achieve the desired dose andeffect. In another example, the ratio of the amount of phenylephrinewith the immediate release forms to the amount of phenylephrine coatedon the delayed release particles can be greater than about 1:1. Inanother example, the ratio of the amount of phenylephrine with theimmediate release forms to the amount of phenylephrine coated on thedelayed release particles can be less than about 1:1. And in anotherexample, the ratio of the amount of phenylephrine with the immediaterelease forms to the amount of phenylephrine on the delayed releaseparticles can be equal to about 1:1. In one example, the ratio of theamount of phenylephrine with the immediate release forms to the amountof phenylephrine coated on the delayed release particles can be fromabout 1:4 to about 4:1, in another example from about 1:3 to about 3:1,and in another example from about 1:2 to about 2:1. In another example,the ratio of the amount of phenylephrine with the immediate releaseforms to the amount of phenylephrine coated on delayed release particlescan be greater than about 1:5, in another example greater than about1:4, in another example greater than about 1:3, in another examplegreater than about 1:2 and in another example greater than about 1:1. Ifthe ratio is not optimal, then the product may not achieve the desireddosing regimen, e.g. once every 6-12 hours.

In another example, the amount of phenylephrine on each immediaterelease particle or other immediate release forms can be different thanthe amount of phenylephrine on each delayed release particle. In anotherexample, the immediate release particles or other immediate release formcan contain more phenylephrine than the delayed release particles andthe amount of phenylephrine is adjusted via the amount coated onto eachparticle. In another example, the immediate release particles or otherimmediate release forms can contain less phenylephrine than the delayedrelease particles and the amount of phenylephrine is adjusted via theamount coated onto each particle. In another example, the immediaterelease particles or other immediate release form can containapproximately the same amount of phenylephrine as the delayed releaseparticles.

The ratio of immediate release particles or other immediate release formto delayed release particles can be adjusted depending on the desired PKprofile. In one example, the PK profile can be substantially equivalentto an immediate release dose form administered every four hours. Inanother example, the PK profile is greater than the PK profile ofmultiple immediate release dose forms administered every four hours andis considered safe and effective for an OTC decongestion product. Inanother example, the PK profile is not substantially equivalent to a thePK profile of multiple immediate release dose forms administered everyfour hours but is considered to be safe and effective for an OTCdecongestion product.

In one example, the multi-particle dosage form can have two pulses, canbe administered every eight hours, and can be substantially equivalentto the PK profile for two four hour doses of a commercially availablephenylephrine product. In another example, the multi-particle dosageform can have two pulses, can be administered every eight hours, and canhave a minimum PK profile that is substantially bioequivalent to the PKprofile for two four hour doses of a commercially availablephenylephrine product. In another example, the multi-particle dose formcan contain both immediate and delayed release phenylephrine particlesand can be administered every 6-8 hours and can have a PK profile thatsubstantially surpasses the PK profile phenylephrine from commerciallyavailable phenylephrine product dosed every 4 hours. In one example theimmediate release particles or other immediate release form and thedelayed release particles can have the same amount of phenylephrine, theweight ratio of immediate release particles to delayed release particlescan be from about 1:1 to about 10:1, in another example the weight ratiocan range from about 1:1 to about 4:1.

In one example the dosage form can contain immediate release particlesor other immediate release forms that can contain from about 5 mg toabout 40 mg phenylephrine hydrochloride, in another example from about 7mg to about 30 mg, and in another example from about 8 mg to about 15mg. In one example, the dosage form can contain immediate releaseparticles or other immediate release forms that can contain 10 mgphenylephrine hydrochloride. In another example the dosage form cancontain immediate release particles or other immediate release formsthat can contain from about 10 mg to about 20 mg phenylephrinehydrochloride, in another example from about 12 mg to about 18 mgphenylephrine hydrochloride, and in another example from about 14 mg toabout 16 mg phenylephrine hydrochloride. The dosage form can containimmediate release particles or other immediate release forms that cancontain 15 mg phenylephrine hydrochloride. In another example the dosageform can contain immediate release particles or other immediate releaseforms that can contain from about 10 mg to about 75 mg phenylephrinehydrochloride, in another example from about 15 mg to about 50 mg, inanother example from about 20 mg to about 40 mg and in another examplefrom about 25 mg to about 35 mg. In one example, the immediate releaseparticles or other immediate release forms can contain about 10 mgphenylephrine, in another example about 15 mg phenylephrine, and inanother example about 20 m phenylephrine.

In another example the dosage form can contain delayed release particlesthat can contain less phenylephrine than the immediate release particlesor other immediate release forms. In another example, the delayedrelease particles can contain less than about 20 mg of phenylephrine, inanother example less than about 15 mg phenylephrine, and in anotherexample less than about 10 mg phenylephrine. In another example thedelayed release particles can contain from about 2 mg to about 9 mgphenylephrine, in another example from about 3 mg to about 7 mgphenylephrine, and in another example from about 4 mg to about 6 mg ofphenylephrine. In another example, the delayed release particles cancontain from about 1 mg to about 5 mg phenylephrine, in another examplefrom about 2 mg to about 4 mg, and in another example about 3 mg. Inanother example, the delayed release particles can contain from about 2to about 7 mg phenylephrine, in another example about 3 mg to about 6mg, and in another example about 5 mg. In another example, the delayedrelease particles can contain from about 3 mg to about 9 mgphenylephrine, in another example from about 5 mg to about 8 mg, and inanother example about 7 mg. The dosage form can contain immediaterelease particles or other immediate release forms that can contain 15mg phenylephrine hydrochloride. In another example the dosage form cancontain immediate release particles or other immediate release formsthat can contain from about 10 mg to about 75 mg phenylephrinehydrochloride, in another example from about 15 mg to about 50 mg, inanother example from about 20 mg to about 40 mg and in another examplefrom about 25 mg to about 35 mg. In one example, the delayed releaseparticles can contain about 10 mg phenylephrine, in another exampleabout 15 mg phenylephrine, and in another example about 20 mphenylephrine.

In one example, the delayed release particles and the immediate releaseparticles or other immediate release forms can contain about the sameamount of phenylephrine. In another example, the delayed releaseparticles can contain more phenylephrine than the delayed releaseparticles. In another example, the delayed release particles can containless phenylephrine than the delayed release particles.

In another example, the pulsatile PE dose can meet or exceed thebioequivalence ranges (>125% AUC) relative to a commercially available,immediate release PE dose taken at 4 hour intervals while remaining safeand effective. In one example, the pulsatile PE dose can exceed thebioequivalency by at least about 5%, in another example by at leastabout 10%, in another example by at least about 15%, in another exampleby at least about 20%, in another example by at least about 25%, inanother example by at least about 30%, in another example at least about40%, in another example by at least about 45%, and in another example atleast about 50%. In one example the pulsatile PE dose can exceedbioequivalency by less than about 75%, in another example by less thanabout 70%, in another example by less than about 65%, in another exampleby less than about 60%, in another example by less than about 55%, inanother example by less than about 50%, in another example by less thanabout 40%, in another example by less than about 35%, in another exampleby less than about 30%, in another example by less than about 25%, inanother example less than about 20%, in another example less than about15%, and in another example less than about 10%. In another example, thepulsatile PE dose can exceed the bioequivalency by at least about 75%,in another example by at least about 100%, in another example by atleast about 150%, in another example by at least about 200%, in anotherexample by at least about 250%, in another example by at least about500%, and in another example by at least about 750%.

As used herein, exceeds bioequivalency may include significant increasesin one or more pharmacokinetic parameters including C_(max) and/or AUCof unconjugated phenylephrine. For example, exceeds bioequivalency caninclude a greater than 2 fold increase in C_(max) and/or AUC ofunconjugated phenylephrine, in another example a greater than 3 foldincrease, in another example a greater than 4 fold increase, in anotherexample a greater than 5 fold increase, in another example a greaterthan 6 fold increase, in another example a greater than 7 fold increase,in another example a greater than 8 fold increase, in another example agreater than 9 fold increase, and in another example a greater than 10fold increase. In one example, dosage forms that exceed bioequivalencycan be safe and efficacious.

The dosage form can contain an immediate release dose in any form. Inone example the immediate release dose can be coated on an immediaterelease particles. In one example, the immediate release dose is not animmediate release particle. In another example, the immediate releasedose can be in a liquid. In another example the immediate release dosecan be a liquid and in another example, the delayed release particlesare suspended in the liquid. In another example, the immediate releasedose can be a combination of forms.

In another example, the immediate release dose can be a separate dosageform, for instance a tablet or a liquid and in one example the immediaterelease dose form is separate and taken concurrently with the extendedrelease particles.

In another example, the immediate release dose can be a granule thatcontains the active and optionally excipients for stability andprocessing. In the immediate release granules, the actives andexcipients can be dispersed, possibly approximately evenly dispersed,throughout the granules. In one example, the granules do not contain acoating. In another example, the granules do not contain an activecoating.

The dosage form can contain immediate release particles or otherimmediate release forms comprising phenylephrine or salts thereof anddelayed release particles comprising phenylephrine or salts thereof. Anypharmaceutically acceptable salt of phenylephrine can be administered.Non-limiting examples of phenylephrine or salts thereof can includephenylephrine hydrochloride, phenylephrine bitartrate, phenylephrinetannate, and combinations thereof. In one example, the dosage form cancontain phenylephrine hydrochloride.

In addition to comprising phenylephrine, the dosage forms can containone or more drug actives in addition to phenylephrine. In one example,the drug actives can be immediate release drug actives, extended releasedrug actives, and/or delayed release drug actives. In one example, theadditional drug active can be formulated as particles.

In one example, the additional drug active is a multi-symptom relief(MSR) cold/flu active which can be used to treat one or more cold/flusymptoms. MSR cold/flu actives can be used to treat a variety ofcold/flu symptoms including nasal congestion, runny nose, sneezing,headache, dry cough, sore throat, sinus pressure or pain, chestcongestion, muscle aches/pains, wet/chesty cough, fever, andcombinations thereof. MSR cold/flu actives can include decongestants,expectorants, antihistamines, antitussives, pain relievers, andcombinations thereof.

Non-limiting examples of expectorants can include guaifenesin, ambroxol,bromhexine, and combinations thereof.

Non-limiting examples of antihistamines can include chlorpheniramine,desloratadine, levocetirizine, diphenhydramine, doxylamine,triprolidine, clemastine, pheniramine, brompheniramine,dexbrompheniramine, loratadine, cetirizine and fexofenadine, amlexanox,alkylamine derivatives, cromolyn, acrivastine, ibudilast, bamipine,ketotifen, nedocromil, omalizumab, dimethindene, oxatomide, pemirolast,pyrrobutamine, pentigetide, thenaldine, picumast, tolpropamine,ramatroban, repirinast, suplatast tosylate aminoalkylethers, tazanolast,bromodiphenhydramine, tranilast, carbinoxamine, traxanox,chlorphenoxamine, diphenylpyaline, embramine, p-methyldiphenhydramine,moxastine, orphenadrine, phenyltoloxamine, setastine, ethylenediaminederivatives, chloropyramine, chlorothen, methapyrilene, pyrilamine,talastine, thenyldiamine, thonzylamine hydrochloride, tripelennamine,piperazines, chlorcyclizine, clocinizine, homochlorcyclizine,hydroxyzine, tricyclics, phenothiazines, mequitazine, promethazine,thiazinamium methylsulfate, azatadine, cyproheptadine, deptropine,desloratadine, isothipendyl, olopatadine, rupatadine, antazoline,astemizole, azelastine, bepotastine, clemizole, ebastine, emedastine,epinastine, levocabastine, mebhydroline, mizolastine, phenindamine,terfenadine, tritoqualine, and combinations thereof.

Non-limiting examples of antitussives can include dextromethorphan,menthol, codeine, chlophedianol, levodropropizine, and combinationsthereof.

Non-limiting examples of pain relievers can include acetaminophen,ibuprofen, ketoprofen, diclofenac, naproxen, aspirin, and combinationsthereof.

In one example, the expectorant can be guaifenesin and in one examplethe dosage form can contain 200 mg of guaifenesin. In one example, theantihistamine can be chlorpheniramine and in one example the dosage formcan contain 125 mg of chlorpheniramine. In one example the antitussivecan be selected from the group consisting of dextromethorphan,chlophedianol, and combinations thereof. In one example the dosage formcan contains 10 mg of dextromethorphan and in another example the dosageform can contain 12.5 mg chlophedianol. In one example the painrelievers can include acetaminophen, ibuprofen, naproxen, orcombinations thereof. In one example the dosage form can contain 325 mgto 500 mg acetaminophen, in another example 200 mg ibuprofen, and inanother example, 200 mg naproxen. In one example, the cold/flu dosageunit can further comprise a stimulant such as caffeine.

In one example, the dosage units can contain one or more MSR cold/fluactives, in another example two or more MSR cold/flu actives, in anotherexample three or more MSR cold/flu actives, and in another example fouror more MSR cold/flu actives. In one example, the dosage unit cancontain exactly one MSR cold/flu active, in another example exactly twoMSR cold/flu actives, in another example exactly three MSR cold/fluactives, and in another example exactly four MSR cold/flu actives. Inone example the dosage units can contain acetaminophen, dextromethorpan,and phenylephrine.

Krebs Buffer Dissolution Method

The Krebs Buffer Dissolution Method can be used to approximate therelease rate of phenylephrine in the digestive tract, in vitro. Testingis performed using the Type II (paddles) dissolution apparatus, asdescribed in USP <711> (Dec. 1, 2013).

Assemble the apparatus then place 500 mL of 0.1N HCl into each of 6vessels. Cover the vessels and allow the medium to equilibrate to atemperature of 37±0.5° C. Place one gelatin capsule containing delayedrelease particles into each vessel and commence dissolution testing.Operate the paddle speed at 50 revolutions per minute (RPM) for twohours. Stainless steel, spring style capsule sinkers that are 23 mm longby 8 mm wide (commercially available as Sotax style sinker, part #CAPWST-23 from QLA, Telford, Pa.) are used to prevent the capsules fromfloating in the vessels.

After two hours of dissolution in 0.1N HCl, withdraw a 10 mL aliquot ofsample from each vessel using separate 10 cc syringes connected tostainless steel cannulae with attached 10 μm filters (available fromQLA). Transfer each filtered acid phase sample into separate HPLC vialsfor analysis.

Then proceed immediately to the Krebs Buffer Stage of dissolutiontesting. This portion of the method requires a complete media exchange.Carefully transfer the undissolved particles and sinkers from each acidphase vessel to an apparatus containing 1000 mL pH 7.4 Krebs buffermedia into each of six vessels. Table 4, below, shows the composition ofKrebs buffer. The Krebs buffer is prepared fresh at time of use. The pHof the media in each vessel is adjusted to 7.40±0.05 prior to startingthe test using a sparging cannulae connected to a supply of carbondioxide gas. This gas is sparged directly into the vessels to lower thepH to the target value. The buffer should also be equilibrated to37±0.5° C. prior to starting the test. Throughout the entire test, gasis sparged into the vessels as needed at low pressure to maintain the pHwithin 7.40±0.05. The pH level inside the vessel is monitored by aportable pH meter.

TABLE 4 Buffer Component Millimolar (mM) Grams per liter Sodium chloride118.07 6.900 Potassium chloride 4.69 0.350 Magnesium sulfate 1.18 0.142Calcium chloride dihydrate 2.52 0.370 Potassium phosphate 1.18 0.161Sodium bicarbonate 24.00 2.016

The apparatus is operated at 50 RPM for up to eight hours. A 10 mLaliquot of sample is removed at appropriate intervals (e.g. every 30minutes) with a separate 10 cc syringe connected to a stainless steelcannula with attached 10 μm filter (available from QLA).

Then use the HPLC-UV Assay, as described herein, is used to determinethe percent dissolved values of phenylephrine in each sample aliquot.

HPLC Dissolution Assay

This method is applicable for the determination of phenylephrine insample aliquots from the Krebs Buffer Dissolution Method. The samplesare analyzed by HPLC with UV detection. The HPLC column is an AgilentZorbax Rapid Resolution, Catalog # HP863953-902, SB-C18, 3.5 μm, 4.6×150mm.

First, the stock and working standard solutions are prepared. Thesesolutions should be prepared fresh at time of use.

Standard Solution Preparation

Stock Solution (0.2 mg/mL)

Weigh 40.00±2 mg of Phenylephrine Reference Standard and transfer to a200 mL volumetric flask. Add approximately 20 mL of water and gentlyswirl, or sonicate if necessary, to dissolve. Dilute to volume withwater and mix well.

Acid Working Standard Solution (0.004 mg/mL)

Dilute stock solution 1:50 by adding 2 mL of stock solution into a 100mL volumetric flask, and bringing to volume with 0.1N HCl aciddissolution media. Mix well.

pH 7.4 Working Standard Solution (0.01 mg/mL)

Dilute stock solution 1:20 by adding 5 mL of stock into a 100 mLvolumetric flask, and bringing to volume with pH 7.4 Krebs buffer media.Mix well.

Set up the HPLC system as per the Chromatic Conditions, in Table 5,below.

TABLE 5 % A % B Time (min) (0.1% TFA) (Acetonitrile) Gradient Conditions0.0 96 4 3.5 96 4 3.6 50 50 4.5 50 50 4.6 96 4 7.0 96 4 Run Time: 7minutes Linear Gradient Column Temperature (° C.) 40 Sample compartmentAmbient temperature Flow Rate (mL/min) 1.5 Detector Wavelength (nm) 275Injection volume (μL) 50

When the baseline stabilizes, inject at least one 0.1N HCl blank,followed by at least one injection of the 0.1N HCl working standardsolution to equilibrate the system.

Once the system is equilibrated, make 5 injections of the acid workingstandard solution and evaluate System Suitability Requirements 1-3,below.

Next, inject the acid-phase samples. Inject a bracketing standard atleast after every sixth acid-phase sample and after the last acid-phasesample. Evaluate System Suitability Requirement 4, below, for allacid-phase bracketing standard injections made throughout the run. Usethe overall average peak area from all acid standard injections madethroughout the run to calculate the acid-phase sample results.

After completing the acid-phase sample analysis, continue on to run thebuffer-phase analyses. As with the acid-phase analysis, eachbuffer-phase analysis must be performed with discrete quantitationagainst the respective pH-matched blank and standards. Begin with atleast one injection of the buffer blank solution (pH 7.4 Krebs Bufferdissolution media). Next, make 5 injections of the corresponding pH 7.4working standard solution followed by the respective sample injections.Make a bracketing buffer standard injection at least every sixth andafter the last respective buffer sample. Evaluate System SuitabilityCriteria 4 for all buffer-phase bracketing standard injections madethroughout the run. Then, the average peak area for all for all bufferstandard injections is calculated and used in the equations below tocalculate the sample results.

System suitability may be calculated after the chromatographic sequencehas been run. If the system suitability results fail to meetRequirements 1-3 for the acid working standard solution, then all data(acid and Krebs buffer) must be rejected and the sequence repeated. If abracketing standard fails to meeting Requirement 4, then thecorresponding samples bracketed by that standard must be rejected andthe analysis repeated.

System Suitability Requirements

-   -   1. Peak Tailing Factor—the tailing factor must be 2.0 or less        for the first acceptable acid standard injection.    -   2. Peak Area Repeatability—The Relative Standard Deviation (RSD)        for the peak area responses must be 2% or less for the first        five acceptable acid standard injections.    -   3. Peak Retention Time Repeatability—The RSD for the peak        retention times must be 2% or less for the first five acceptable        acid standard injections.    -   4. Overall Standard Peak Area Repeatability—The overall % RSD of        the peak areas for all standard injections made throughout the        run (5 initial injections plus bracketing standards) must be 2%        or less.

Calculations

${\% \mspace{14mu} {{Dissolved}\left( {{Acid} - {Phase}} \right)}} = {\frac{{Peak}\mspace{14mu} {Area}\mspace{14mu} {Sample}}{{Avg}\mspace{14mu} {Peak}\mspace{14mu} {Area}\mspace{14mu} {Working}\mspace{14mu} {Std}} \times {Acid}\mspace{14mu} {Working}\mspace{14mu} {Std}\mspace{14mu} {{Conc}\left( \frac{mg}{mL} \right)} \times \frac{500\mspace{14mu} {mL}}{{Dose}\mspace{14mu} {{Strength}({mg})}} \times 100}$${\% \mspace{14mu} {{Dissolved}\left( {{Buffer} - {Phase}} \right)}} = {\frac{{Peak}\mspace{14mu} {Area}\mspace{14mu} {Sample}}{{Avg}{\mspace{11mu} \;}{Peak}\mspace{14mu} {Area}\mspace{14mu} {Working}\mspace{14mu} {Std}} \times {Buffer}\mspace{14mu} {Working}\mspace{14mu} {Std}\mspace{14mu} {{Conc}\left( \frac{mg}{mL} \right)} \times \frac{1000\mspace{14mu} {mL}}{{Dose}\mspace{14mu} {{Strength}({mg})}} \times 100}$

If active is released during the acid phase, the pH 7.4 buffer phase %dissolved value needs to be corrected to account for active loss duringthe media exchange. The acid phase portion of the test (sample taken at2 hours) should have no active release. The % dissolved value should bezero. If it is not, then this value needs to be added to all bufferphase results.

Smoothness Test Method

The Smoothness Test Method can be used to determine the circularity ofthe particles. Circularity is determined by (4π×([Area])/([Perimeter]²)and ranges from 0 (infinitely elongated polygon) to 1 (perfect circle).Thus, a particle with a rough, coarse, or spiked appearance can have alarger perimeter value as compared to a smooth particle with the samearea. Therefore, differences in surface topology can be calculated usingthe differences in the obtained circularity results.

Using a microscope (Nikon OPTIPHOT-2) and 40× magnification (4×magnifier and 10× eyepiece) and a digital camera (OptixCam SummitOCS-10.0) designed for microscopy, select the field of view thatcontains the particles to be analyzed. There should be spaces betweenthe particles in the selected field of view.

The image is saved in an acceptable file format, such as JPEG, andopened using ImageJ 1.49v (Image Processing and Analysis in Java)computer software using the “File/Open” menu pointed to the stored filedirectory.

Next, adjust the settings on ImageJ. Open the threshold settings paneland select the following: method (Default), Color (B&W), and Color Space(HSB).

The next step is to tune the white background and black particles tomake sure that the images to be studied are completely filled within theoutline masks. This is done using the brightness sliders in the softwareprogram. Slide the brightness slider so snow appears in the background,as in FIG. 10 A. Then, slide the brightness adjustments just until thebackground becomes white again, without any snow, as in FIG. 10B.

The image is ready for measurement processing. Using the “SetMeasurements” menu, assign the measurements t be taken for the image.For this test, “Shape descriptors” must be checked for circularity androundness measurements. Then, use the “Analyze Particles” command fromthe “Analyze” menu to select a size filter, to omit any small particlesto not be included in measurement. This is done by selecting size(pixel̂2): 500-Infinity. In the “Analyze Particles” command, also selectdisplay results, clear results, summarize, exclude on edges, and includeholes. Exclude on edges will not include any thresholded particles onthe edge of the image, only those within full view. Also select Show:“Overlay Outlines” to create new image with analyzed particleshighlighted for easy reference. Now, select “OK” to analyze theparticles. An image summary report and outline overlay of the originalimage will be displayed.

Repeat ten times with each population of particles, changing the fieldof view each time and calculate the mean circularity.

Examples

Ex. 1 Ex. 2 Ex. 3 Ex. 4 Treatment 4 Treatment 1 Treatment 3 Treatment 2PE Coated Cellets   700 g   700 g   700 g   700 g Eudragit ® FS 30D¹1212.0 g 1020.9 g 1084.7 g 1020.9 g Eudragit ® L30D-55²    0 g  180.6 g 120.8 g  180.6 g Polysorbate 80   3.6 g   3.5 g   3.6 g   3.5 gTriethyl Citrate  18.0 g  20.7 g  19.9 g  20.7 g Glycerol Monostearate 14.4 g  15.0 g  14.9 g  15.0 g Purified Water  752.0 g  758.8 g  756.4g  758.8 g Total Solution 2000.0 g 1999.5 g 2000.3 g 1999.5 g GramsSprayed 1029.2 g 1028.7 g 1043.7 g 1732.3 g Target Batch Size  905.6 g 905.6 g  908.7 g 1046.2 g Wt % Increase 29.4% 29.4% 29.8% 49.5% Wt % ofpH Sensitive 22.7% 22.7% 23.0% 33.1% Coating 10 mg IR/3 mg 10 mg IR/5 mg10 mg IR/5 mg 10 mg IR/7 mg delayed release delayed release delayedrelease delayed release (50% pH coating) (40% pH coating) (50% pHcoating) (50% pH coating) capsules capsules capsules capsules Example: 56 7 8 % mg % mg % mg % mg Delayed Release Particle Phenylephrine HCl2.62 3 4.38 5 4.07 5 5.58 7 Cellets 500 (microcrystalline 55.55 63.6758.23 66.43 54.1 66.43 52.58 65.92 cellulose core) Kollicoat ® IR(solids) 3.81 4.36 4.1 4.67 3.81 4.67 3.81 4.77 Talc 1.9 2.18 2.05 2.341.9 2.34 1.9 2.39 Eugradit FS30D 31.94 36.6 27.5 31.38 31.94 39.22 31.9440.04 PlasACRYL ™ T20 3.19 3.66 2.75 3.14 3.19 3.92 3.19 4 (TriethylCitrate) 1.68 1.92 1.44 1.65 1.68 2.06 1.68 2.1 (Glycerol monostearate1.34 1.54 1.15 1.32 1.34 1.65 1.34 1.68 (Polysorbate 80) 0.18 0.2 .15.18 .18 0.22 .18 0.22 Aerosil ® 200 (SiO2) 0.99 1.13 0.99 1.13 0.99 1.220.99 1.24 Immediate Release Particle Phenylephrine HCl 8.66 10 8.66 108.66 10 8.66 10 Cellets 500 (microcrystalline 81.51 94.17 81.51 94.1781.51 94.17 81.51 94.17 cellulose core) Kollicoat ® IR (solids) 5.9 6.815.9 6.81 5.9 6.81 5.9 6.81 Talc 2.95 3.41 2.95 3.41 2.95 3.41 2.95 3.41Aerosil ® 200 (SiO2) 0.99 1.14 0.99 1.14 0.99 1.14 0.99 1.14 10 mg IR/5mg 10 mg IR/7 mg 10 mg IR/7 mg delayed release delayed release delayedrelease (60% pH coating) (40% pH coating) (50% pH coating) capsulescapsules capsules Example: 9 10 11 % mg % mg % mg Delayed ReleaseParticle Phenylephrine HCl 3.8 6.01 5.58 7 7 5 Cellets 500(microcrystalline 50.51 56.6 52.58 65.92 65.92 66.43 cellulose core)Kollicoat ® IR (solids) 3.55 4.1 3.81 4.77 4.77 4.67 Talc 1.78 2.05 1.92.39 2.39 2.34 Eugradit FS30D 35.79 27.5 31.94 40.04 32.03 47.06PlasACRYL ™ T20 3.58 2.75 3.19 4 3.2 4.71 (Triethyl Citrate) 1.88 1.441.68 2.1 1.68 2.47 (Glycerol monostearate 1.5 1.15 1.34 1.68 1.34 1.97(Polysorbate 80) 0.2 .15 .18 0.22 .18 0.26 Aerosil ® 200 (SiO2) 0.990.99 0.99 1.24 1.15 1.3 Total: 100 100 100 125.35 116.46 131.51Immediate Release Particle Phenylephrine HCl 8.66 10 8.66 10 8.66 10Cellets 500 (microcrystalline 81.51 94.17 81.51 94.17 81.51 94.17cellulose core) Kollicoat ® IR (solids) 5.9 6.81 5.9 6.81 5.9 6.81 Talc2.95 3.41 2.95 3.41 2.95 3.41 Aerosil ® 200 (SiO2) 0.99 1.14 0.99 1.140.99 1.14 Total: 100 115.53 100 115.53 100 115.53 10 mg IR/10 mg 10 mgIR/15 mg 10 mg IR/20 mg 15 mg IR/15 mg delayed release delayed releasedelayed release delayed release (45% pH Coating) (45% pH Coating) (45%pH Coating) (45% pH Coating) capsules capsules capsules capsules Example12 13 14 15 % mg % mg % mg % mg Delayed Release Fill Phenylephrine HCl7.91 10.00 11.11 15.00 11.11 20.00 11.11 15.00 Cellets 500(microcrystalline 52.02 65.76 48.82 65.91 48.82 87.87 48.82 65.91cellulose core) Kollicoat IR (solids) 4.20 5.30 4.20 5.66 4.20 7.55 4.205.66 Talc 2.10 2.65 2.10 2.83 2.10 3.78 2.10 2.83 Eugradit FS30D 29.8037.67 29.80 40.23 29.80 53.64 29.80 40.23 PlasACRYL T20 2.98 3.77 2.984.02 2.98 5.36 2.98 4.02 (Triethyl Citrate) 1.56 1.98 1.56 2.11 1.562.81 1.56 2.11 (Glycerol monostearate 1.25 1.58 1.25 1.69 1.25 2.25 1.251.69 (Polysorbate 80) 0.17 0.21 0.17 0.23 0.17 0.30 0.17 0.23 Aerosil200 (SiO2) 0.99 1.25 0.99 1.34 0.99 1.78 0.99 1.34 Total: 100.00 126.40100.00 134.99 100.00 179.99 100.00 134.99 Immediate Release FillPhenylephrine HCl 8.60 10.00 8.60 10.00 8.60 10.00 11.83 15.00 Cellets500 (microcrystalline 81.00 94.17 81.00 94.17 81.00 94.17 77.77 98.64cellulose core) Kollicoat IR (solids) 6.27 7.29 6.27 7.29 6.27 7.29 6.277.95 Talc 3.14 3.65 3.14 3.65 3.14 3.65 3.14 3.98 Aerosil 200 (SiO2)0.99 1.15 0.99 1.15 0.99 1.15 0.99 1.26 Total: 100 116.26 100 116.26 100116.26 100.00 126.82 ^(1,2)Available from Evonik Industries (Darmstadt,Germany)

Examples 1-4 were made as follows. First, 7000 grams (g) of Cellets® 500(available from Glatt® Air Techniques Inc., Ramsey, N.J.) were spraycoated with an aqueous solution containing 1235.0 g phenylephrinehydrochloride dissolved in 11,115 g of purified water and then dried ina GPCG-5 fluid bed column with 9 inch Wurster Insert (available fromGlatt® Air Techniques, Ramsey, N.J.). The fluid bed column was attachedto a calibrated pump set at a constant rate of 20-60 grams per minute.The Cellets® with the aqueous coating were then dried in the fluid bedcolumn for five minutes at 20 cubic feet per minute (CFM) at atemperature between 35 degrees Celcius (° C.) and 45° C. to form thephenylephrine hydrochloride (PE-HCl) coated Cellets®.

In a separate container, polysorbate 80, triethylcitrate, andglycerolmonostearate were combined in 540 g of purified water. Thepolysorbate 80, triethylcitrate, and glycerolmonostearate mixture washeated by a hot plate between 70° C. and 80° C. and stirred with apropeller mixer. After the ingredients were dissolved, the solution wascooled to room temperature, which was less than 33° C., and purifiedwater was added to produce approximately 2000 g of solution. In Example1, 212 g of purified water was added so the total solution weighed 2000g. Then the Eudragit® FS-30D was added to the solution (available fromEvonik Industries, Darmstadt, Germany) and was stirred with a propellermixer for 60 min to form Dispersion 1.

In Example 1, Dispersion 1 was sprayed onto 700 g of the PE-HCl coatedCellets® using a calibrated pump sprayer attached to a fluid bed columnset to a rate between 20-60 grams per min. The spray coating wasperformed within the GPCG-5 fluid bed column with a 6″ Wurster insert at45±10° C. 905.6 g of coated particles were obtained after drying for 5min in the same fluid bed column with an air inlet temperature of 45±10°C.

For Examples 2, 3, and 4 the process of dissolving the polysorbate 80,triethylcitrate, and glycerolmonosterate from above was repeated andthen the Eudragit® L30D-55 was added as described above to formDispersion 2.

In Examples 2, 3, and 4, Dispersion 1 and 2 were combined into a singlecontainer and stirred at room temperature for 45 minutes using apropeller mixer. The final volume was adjusted with purified water toproduce approximately 2000 g of the combined total solution. Thecombined total solution was then screened through a US 60 mesh screeninto a clean container and stored at room temperature and was stirredcontinuously until use. The combined total solution was used within 48hours after it was screened.

Next, the combined total solution was sprayed onto 700 g of the PE-HClcoated Cellets® and dried for five minutes as described above. 900-1050grams, depending on the weight percent of the coating, of coatedparticles were obtained after drying for five minutes as describedabove.

Examples 5-15 include both immediate release and delayed releaseparticles. As a first step, drug layered particles were produced using abatch size of 7000 g of Cellets® 500. PE-HCl spray solutions wereprepared in an appropriately sized vessel with mixing element viadissolving PE-HCl in water to produce a 22.5% concentrated solution.Depending on the example, particles were drug layered in a GPCG-5 fluidbed with 9″ Wurster insert to yield particles having a final PE-HClconcentration of 4.5%, 7.0%, 9.6%, 13.2%, and 18.54%. The processconditions for drug layering included a 55° C. inlet air temperature,40° C. product temperature, 150 CFM air flow rate, and ramping to a 26g/min spray rate.

After a one minute drying step, the drug layered particles from examples5-11 are then seal coated with a coating spray of 15% Kollicoat® IR and7.5% talc to a weight gain of 7% based on the Kollicoat® IR polymer. Thespray composition is prepared as follows: 59% of the total water wasadded to an appropriate sized vessel with a propeller mixer. Kollicoat®IR was added while mixing for a minimum of 15 minutes. In a separatecontainer, the remaining water is added and set-up with a high shearmixer. The talc was added and mixed to form a dispersion for a minimumof 5 minutes. The talc dispersion was then added to the Kollicoat®mixture and mixed for at least 10 minutes with the propeller mixer. TheWurster process conditions in the same equipment included a 52° C. inletair temperature, 42° C. product temperature, 180 CFM air flow rate, andramping to a 17 g/min spray rate. The seal coated particles were thendried for 5 minutes before discharging or further processing.

Some of the 9.6% PE seal coated particles were topcoated with a 5%Aerosil® 200 suspension to a 1% wt. gain using process conditions in thesame equipment having a 53° C. inlet air temperature, 40° C. producttemperature, 170 CFM air flow rate, and ramping to a 20 g/min sprayrate. The top coated particles were dried for 5 minutes. The 5% Aerosil®200 suspension was prepared by adding water to an appropriate sizedcontainer that includes a propeller mixer. This version is for theimmediate release particle.

The other lots were enteric coated to specified wt. gain of entericpolymer using the GPCG-5 fluid bed with 7″ wurster at a batch size of 2kg of the seal coated particles (vide supra). The enteric coateddispersion is made as follows: Water was added to PlasACRYL™ T200 andmixed for 10 minutes minimum in an appropriate sized mixing vessel withtri-blade mixer. While mixing, the Eudragit® FS30D polymer was added andmixed for 5 minutes minimum to make a uniform dispersion. The mixturewas passed through a #60 US standard sieve to remove any clumps present.The process conditions used include a 39° C. inlet air temperature, 30°C. product temperature, 160 CFM air flow rate, and ramping to a 22 g/minspray rate. The enteric coated particles were dried for one minute.

The enteric coated particles were then top coated with a 5% Aerosil® 200suspension (made as above) to a 1% wt. gain using process conditions inthe same equipment having a 39° C. inlet air temperature, 30° C. producttemperature, 160 CFM air flow rate, and ramping to a 18 g/min sprayrate. The top coated particles were then dried for 5 minutes. Thisversion is for the delayed release particle.

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “40 mm” is intended to mean“about 40 mm.”

Every document cited herein, including any cross referenced or relatedpatent or application is hereby incorporated herein by reference in itsentirety unless expressly excluded or otherwise limited. The citation ofany document is not an admission that it is prior art with respect toany invention disclosed or claimed herein or that it alone, or in anycombination with any other reference or references, teaches, suggests ordiscloses any such invention. Accordingly, all numerical values areunderstood to be modified by the term “about.” Further, to the extentthat any meaning or definition of a term in this document conflicts withany meaning or definition of the same term in a document incorporated byreference, the meaning or definition assigned to that term in thisdocument shall govern.

While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this invention.

What is claimed is:
 1. A dose of a multi-particle oral dosage form forthe delivery of phenylephrine in controlled pulsed doses comprising: a.an immediate release form comprising phenylephrine or a salt thereof;and b. a plurality of delayed release particles comprising a coatingcomprising phenylephrine or salt thereof and a pH sensitive coatingcomprising a polymer; wherein the AUC meets or exceeds the AUC for two10 mg immediate release phenylephrine doses taken four hours apart. 2.The dose according to claim 1 wherein the delayed release particlescomprise from 15 wt. % to 65 wt. % of pH sensitive coating, by weight ofthe delayed release particles.
 3. The dose according to claim 1 whereinthe pH sensitive coating is an enteric coating.
 4. The dose according toclaim 1 wherein the polymer is an acrylic acid ester co-polymer.
 5. Thedose according to claim 1 wherein the plurality of delayed releaseparticles comprise from about 10 mg to about 20 mg phenylephrine.
 6. Thedose according to claim 5 wherein the plurality of delayed releaseparticles comprise from about 12 mg to about 18 mg phenylephrine.
 7. Thedose according to claim 1 wherein the immediate release form comprisesfrom about 10 mg to about 20 mg phenylephrine.
 8. The dose according toclaim 7 wherein the plurality of immediate release form comprises fromabout 12 mg to about 18 mg phenylephrine.
 9. The dose according to claim1 further comprises a second drug active wherein the second drug activeis an immediate release drug active.
 10. The dose according to claim 1wherein the second drug active has a circularity from about 0.7 to about1 as determined by the Smoothness Test Method.
 11. A multi-particle oraldosage form for the delivery of phenylephrine in controlled pulsed dosescomprising: a. an immediate release form comprising phenylephrine or asalt thereof; and b. a plurality of delayed release particles comprisinga coating containing phenylephrine or salt thereof and a pH sensitivecoating comprising a polymer; wherein a lag time as determined by theKrebs Buffer Method is from about 1 hour to about 4 hours.
 12. Thedosage form according to claim 11 wherein the lag time as determined bythe Krebs Buffer Method is from about 1.5 hours to about 2.5 hours. 13.The dosage form according to claim 11 wherein the C_(max) meets orexceeds the C_(max) for two immediate release phenylephrine doses takenfour hours apart.
 14. The dosage form according to claim 11 wherein thedelayed release particles are substantially smooth as visuallyperceivable under a microscope with a total magnification of 40×. 15.The dosage form according to claim 11 wherein of the phenylephrine aratio with the immediate release form to the amount of phenylephrinecoated on the delayed release particles can be greater than or equal toabout 1:1.
 16. The dosage form according to claim 11 wherein theimmediate release form comprises a plurality of coated particles. 17.The dosage form according to claim 11 wherein the immediate release formcomprises a plurality of granules and wherein the phenylephrine isdispersed throughout the granules.
 18. A method of treating nasalcongestion by administering the dose of claim 1 every six to twelvehours.
 19. A method of treating nasal congestion by administering thedose of claim 1 every eight hours.